Apoptosis is programmed cell death and the Bax gene is known to be a potent apoptosis-inducing gene. The Bcl-2 gene is known to be an oncogene which suppresses apoptosis and many Bcl-2 family proteins homologous to Bcl-2 protein are found (Bcl-2, Bcl-xL and the like).
Introducing genes that induce various types of cell death including apoptosis into cancer cells is a promising anti-cancer therapy. It has been reported recently that Bcl-2 family proteins such as Bcl-2, Bcl-xL and the like are expressed in cancer cells and exhibit antagonism to the induction of cell death by the Bax protein. These family proteins exhibit antagonism by binding to Bax protein via the region named BH3 of the Bax protein. The present inventors investigated an N-terminus deleted Bax (ΔNBax) which comprises an amino acid sequence from the 112th amino acid residue to the 192nd amino acid residue of Bax and has lost the N-terminal region including the BH3 region, and reported that ΔNBax is the cell death-inducing domain of the cell death-inducing bax gene product (Biochem Biophys Res Commun. 1998 Feb. 13; 243 (2): 609-616). When located at the downstream of a promoter, expression of the ΔNBax in cells induces cell death, which can not be inhibited by even overexpression of Bcl-xL. The gene coding for ΔNBax, the vector containing the gene and the usage of the ΔNBax peptide for inhibiting the proliferation of cancer cells have been reported (JP Patent Publication (Kokai) No. 2002-355034).
On another front, various homing signal peptides are currently investigated to introduce drugs, such as anti-cancer drugs and the like, into cells specifically. For example, peptides designated as NGR and RGD are known to act selectively on the endothelial cells undergoing angiogenesis (Nat Med. 1999 September; 5(9):1032-1038), and it is possible to use these as specific homing signal peptides for the cell surface receptor of endothelial cells undergoing angiogenesis in cancer tissue.
Presently, cancer is treated mainly by chemotherapy in which anti-cancer drugs are administered, radiotherapy in which an affected lesion is irradiated, immunotherapy in which anti-cancer cell antibodies are administered and gene therapy. However, there are various problematic side effects in chemotherapy and radiation therapy. Also, immunotherapy requires a long period of time and further, gene therapy demands great efforts in developing because of the safety considerations such as uncertainty of the effect of the gene on patients and the like. Thus, cancer therapy in which a large-molecular-weight protein acting directly on cancer cells is directly targeted to the target site has been sought. However, there has been no protein which specifically acts on cancer cells to strongly inhibit the growth of cancer cells and can be surely used for treating cancer. If ΔNBax is specifically interacted with the surface receptor of the endothelial cells undergoing angiogenesis in cancer tissue, it is expected that ΔNBax is utilized as a more effective inhibitor of cancer cell growth, solving the shortcomings of the past treatment method. However, no investigation in this line has conventionally been carried out. ΔNBax itself possesses an apoptosis-inducing activity but its apoptosis-inducing activity has been desired to be enhanced.